This Program Project renewal seeks to build upon the success of the first cycle, where many exciting discoveries were made regarding gene expression in peripheral blood of children with Juvenile Idiopathic Arthritis (JIA). This proposal takes advantage of significant investments made in the first cycle that produced valuable resources for further studies, including a large gene expression dataset, a substantial collection of biological samples (DNA, RNA, whole blood for RNA, peripheral blood mononuclear cells (PBMC) for RNA, plasma, and serum), and a well-developed infrastructure for sample collection and analysis. Among the most important findings of the first cycle was identification of gene expression signatures that indicated heterogeneity among and within several JIA subtypes. These signatures may not only contribute to redefining JIA categories by offering molecular phenotypes, but also may provide insight into fundamental pathobiological processes in JIA, with potential implications for differential responses to treatments, and novel links to understanding genetic susceptibility to JIA. For example, a T Cell Signature expressed in many older polyarticular JIA patients appears to predict inadequate responses to methotrexate, and it is also associated with increased expression of putative JIA susceptibility loci. The four projects proposed in this renewal synergistically approach important questions regarding gene expression in JIA that have been raised by findings in the first cycle; leveraging data, samples and infrastructure developed in the first cycle. In Project 1, Dr. Griffin will investigate cellular pathobiology associated with three gene expression signatures identified in polyarticular and oligoarticular JIA. In Project 2, Dr. Lovell will investigate the relationship of these signatures with clinical responses to methotrexate and anti-TNF biologies, as well as determine if PBMC gene expression profiling can help guide withdrawal of anti-TNF agents from patients in remission on medication. In Project 3, Dr. Thompson will investigate genetic susceptibility loci that have remarkable connections to gene expression differences in JIA. In Project 4, Dr. Grom will use gene expression profiling to study pathobiology of monomyelocytoid cells in systemic-onset JIA. All four projects will be supported by Administrative (Dr. Glass), Tissue (Dr. Thompson), and Informatics (Dr. Wagner) Cores that will facilitate efficient and effective use of resources. Gene expression profiling offers a molecular approach for advancing knowledge of pathobiology, clinical outcomes and genetic associations in JIA, with discoveries made in this Program Project having the potential to dramatically improve diagnosis and management of JIA.